Pathios Therapeutics will team up with researchers at The University of Oxford to accelerate cancer immunotherapies targeting GPR65 on immunosuppressive macrophages

Pathios Therapeutics Limited (“Pathios”), an innovative biotech company focused on the development of first-in-class therapies for cancer, today announced that it has been awarded £350K (approximately US$475K) in the form a Smart Grant from Innovate UK, the UK Government’s innovation agency, to accelerate their cancer immunotherapy programme targeting the innate immune checkpoint, GPR65. Pathios will collaborate on this project with researchers from the Department of Oncology at The University of Oxford to develop the key tools required to enable the rapid translation of small-molecule GPR65 inhibitors for treatment-resistant melanoma.

The advent of immunotherapy agents targeting T-cell checkpoints (PD-1/CTLA-4) has brought about significant improvements in the long-term survival of many melanoma patients. However, only a subset of patients receive sustained benefit from these treatments and it remains an ongoing challenge to identify additional therapies for the remaining non-responsive population.

Recent ground-breaking science suggests a key reason that some melanoma patients that do not respond well to anti-PD-1 therapies relates to the disarming of innate immune cells called tumour-associated macrophages (TAMs) by the acidic microenvironment that is inherent to advanced tumours. Activation of the pH-sensing receptor, GPR65, on TAMs by acidic pH leads to the suppression of a host of pro-inflammatory genes thereby shifting the characteristics of these cells from immune-stimulating to immunosuppressive(1). The importance of the GPR65 pathway in cancer is underscored by a small proportion of the population with inactivating polymorphisms showing stratified association with survival when analysed in The Cancer Genome Atlas (TCGA). Pathios’ ‘Macrophage Conditioning’ approach aims to deploy small-molecule GPR65 inhibitors to reverse pH-dependent immunosuppressive signalling in the vast majority of patients who do not carry this genetic change.

With this grant, Pathios will develop a range of tools to expedite the translation of small molecule GPR65 inhibitors for use in cancer immunotherapy. This will include the development of early clinical target engagement biomarkers as well as employing a range of bioinformatics techniques to identify those patients most likely to benefit from Pathios’ GPR65-targeted approach.

Stuart Hughes, Chief Executive Officer of Pathios: “We are delighted to have secured this highly competitive funding from Innovate UK to accelerate our programme against GPR65 and to continue to build our scientific links with cancer researchers at The University of Oxford. This award boosts our ongoing programme and is a significant endorsement of our novel approach to targeting the innate immune system in hard-to-treat cancers. We look forward to developing the tools that will drive forward our GPR65-based ‘Macrophage Conditioning’ technology and help deliver on the company’s goal to provide a first-in-class treatment approach for those melanoma patients who currently have limited treatment options”.

About Pathios Therapeutics
Launched in 2017, Pathios is a drug discovery and development company focused on translating innovative science into new medicines. Pathios was founded by a team of experienced biotech and pharmaceutical industry professionals, entrepreneurs and clinicians. To date, Pathios has secured a total of US$13.2M in Series A funding from the leading venture capital firms, Canaan Partners and Brandon Capital. The Company is focused on developing small-molecule inhibitors of the pH-sensing G protein-coupled receptor GPR65 to target immunosuppressive macrophages in advanced cancers. The acidic tumour microenvironment, inherent to many cancers, causes a profound immunosuppression of infiltrating immune cells. This environment disarms the anti-cancer immune response and negates the effectiveness of current immunotherapies. This is particularly evident in tumour associated macrophages (TAM), where acidity is sensed by the cell-surface receptor GPR65 leading to an induction of the transcriptional repressor ICER (inducible cAMP early repressor) and the widespread suppression of pro-inflammatory mediators such as TNFalpha, IL-6 and IL-12. Pathios is headquartered in Oxford, UK. For more information, please visit www.pathios.com.

About Innovate UK
Innovate UK drives productivity and economic growth by supporting businesses to develop and realise the potential of new ideas. We connect businesses to the partners, customers and investors that can help them turn ideas into commercially successful products and services and business growth. We fund business and research collaborations to accelerate innovation and drive business investment into R&D. Our support is available to businesses across all economic sectors, value chains and UK regions. Innovate UK is part of UK Research and Innovation. For more information visit www.innovateuk.ukri.org.

1. Bohn et al. (2018) Tumor immunoevasion via acidosis dependent induction of regulatory tumor-associated macrophages. Nature Immunology 19(12):1319-1329.